dorsomorphin and Alzheimer-Disease

The AMP-activated protein kinase (AMPK) is a Ser/Thr kinase that is activated in response to low-energy states to coordinate multiple signaling pathways to maintain cellular energy homeostasis. Dysregulation of AMPK signaling has been observed in Alzheimer's disease (AD), which is associated with abnormal neuronal energy metabolism. In the current study we tested the hypothesis that aberrant AMPK signaling underlies AD-associated synaptic plasticity impairments by using pharmacological and genetic approaches. We found that amyloid β (Aβ)-induced inhibition of long-term potentiation (LTP) and enhancement of long-term depression were corrected by the AMPK inhibitor compound C (CC). Similarly, LTP impairments in APP/PS1 transgenic mice that model AD were improved by CC treatment. In addition, Aβ-induced LTP failure was prevented in mice with genetic deletion of the AMPK α2-subunit, the predominant AMPK catalytic subunit in the brain. Furthermore, we found that eukaryotic elongation factor 2 (eEF2) and its kinase eEF2K are key downstream effectors that mediate the detrimental effects of hyperactive AMPK in AD pathophysiology. Our findings describe a previously unrecognized role of aberrant AMPK signaling in AD-related synaptic pathophysiology and reveal a potential therapeutic target for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Protein Precursor; Animals; Cells, Cultured; Elongation Factor 2 Kinase; Excitatory Postsynaptic Potentials; Female; Hippocampus; Humans; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; Peptide Elongation Factor 2; Presenilin-1; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

Leptin, which serves as a lipid-modulating hormone to control metabolic energy availability, is decreased in Alzheimer's disease (AD) patients, and serum levels are inversely correlated to severity of dementia. We have previously described the effects of leptin in reducing amyloid beta protein both in vitro and in vivo, and tau phosphorylation in vitro. Herein, we systematically investigated the signaling pathways activated by leptin, leading to these molecular endpoints, to better understand its mechanism of action. Inhibition of amyloid beta production and tau phosphorylation in leptin-treated human and/or rat neuronal cultures were both dependent on activation of AMP-activated protein kinase (AMPK). Direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), replicated leptin's effects and conversely, Compound C, an inhibitor of AMPK, blocked leptin's action. The data implicate that AMPK is a key regulator of both AD-related pathways.

Topics: Alzheimer Disease; Aminoimidazole Carboxamide; AMP-Activated Protein Kinase Kinases; Amyloid beta-Peptides; Animals; Cells, Cultured; Humans; Leptin; Neurons; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyrimidines; Rats; Ribonucleotides; tau Proteins

Leptin is a centrally acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid beta levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at amino acid residues Ser(202), Ser(396) and Ser(404) was monitored in retinoic acid induced, human cell lines: SH-SY5Y and NTera-2. Both hormones induced a concentration- and time-dependent reduction of tau phosphorylation, and were synergistic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC(50)L=46.9 nM vs. IC(50)I=13.8 microM). A central role for AMP-dependent kinase as a mediator of leptin's action is demonstrated by the ability of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation, and by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both amyloid beta and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimer's disease.

Topics: Alzheimer Disease; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Cell Line, Tumor; Humans; Insulin; Leptin; Multienzyme Complexes; Neurons; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Ribonucleotides; Signal Transduction; tau Proteins